This is a competitive renewal of a 10-year project that has provided enormous insight into Alzheimer's Disease (AD), a disease that costs $113 billion/yr in the U.S. alone, with no known cure. The project develops a multidimensional, computational atlas of AD. Our 5-year plan of work provides the most powerful computational tools to track AD emerging and spreading in the living brain - years before symptoms begin. We will correlate 3 perspectives on AD in an atlas coordinate framework - serial MRI, novel PET tracers, and 3D pathology. This will provide scientists will the most sensitive approach ever created to gauge which factors affect disease progression (drug treatment, genetic risk, etc.), and how effectively treatments slow the transition to AD. First, we chart the anatomic trajectory of AD with novel analyses of serial MRI (Aims 1,2). Our tools to detect brain changes (cortical thickness mapping, tensor-based morphometry) provided the first time-lapse maps of the disease spreading in the living brain. Here we apply them to MCI subjects (who are at five-fold higher risk of converting to AD in any given year) to identify the best predictors of imminent disease onset, and to predict changes in specific cognitive domains. This will greatly advance drug trials by better identifying candidates for early treatment, who can benefit most before irreversible damage sets in. Next, we will use novel PET tracer molecules to reconstruct the dynamic sequence of AD pathology as it builds up and spreads in the living brain (Aim 3). Hailed as a breakthrough in the AD community, our newly-developed PET (positron emission tomography) tracer compound, [18F]-FDDNP, visualizes amyloid plaques and neurofibrillary tangles (NFTs) - hallmarks of AD previously only detectable at autopsy. Our sensitive surface-based 3D analytic techniques will map the spatio-temporal trajectory of plaque and tangle build-up in aging, mild cognitive impairment, and AD, comparing groups to identify brain changes that predict imminent cognitive deterioration or transition to AD;we will compare and correlate these signals with MRI measures of atrophic rates and cortical degeneration to create joint MR-PET measures of disease burden. We will pioneer 3D cryosection imaging (in 3 subjects/year) to establish how 3D reconstructed maps of tangle density and betaamyloid distribution throughout the brain correlate with imaging measures from living patients. This groundtruth data will be a resource to the AD community, revealing the cellular correlates of imaging signals whose physiological meaning is poorly understood. We will map individuals and populations, revealing group patterns of cortical thinning and plaque and tangle pathology that predict outcomes. Identifying predictors of imminent decline and disease onset, our atlas will identify candidates with emerging pathology for early drug treatment, and will store statistical data to quantify how well treatments resist AD in those at risk. We will share all images, protocols, and algorithms with our 100+ collaborating laboratories.